The autonomic nervous system is the crucial link between the brain and the cardiovascular system. It is the final common pathway by which central disturbances-whether initiated by exogenous psychological or physical stress, or endogenous biochemical or structural perturbation-are translated into alterations in cardiac and vascular function. There is compelling evidence that disordered autonomic engagement of the heart and vasculature contributes importantly to many forms of cardiovascular disease: arrhythmias, sudden death, hypertension, syncope, myocardial infarction, and stroke. The goal of the Program Project is to achieve better understanding of how the brain exerts control over the autonomic nervous system. The integrating theme of this grant is autonomic cardiovascular regulation and the means by which the autonomic nervous system controls effector tissues.. The rationale for the Program Project is the tightly coordinated testing of hypotheses addressing autonomic modulation of cardiovascular function in health and disease. Component projects address central and peripheral autonomic mechanisms, employing both integrated and reductionist approaches. The roles of specific gene products (the choline transporter and ADRA2A adrenoreceptors), and afferent (gastropressor response), efferent (hyperadrenergic hypertension), endocrine (hypoglycemia, exercise), and vascular (nitric oxide) mechanisms are examined. The programmatic approach will facilitate the bidirectional transfer of information between the laboratory and the clinic because it brings together investigators with a wide range of skills who have a track record of discovering new fundamental knowledge and applying it to the creation of practical improvements in health. This Program Project should lead directly to improved therapy in cardiovascular disease.